DESCRIPTION OF THE OVERALL PROGRAM (provided by applicant): Human papillomavirus (HPV) continues to be a major public health problem both in the US and worldwide. From adolescence through adulthood, females are especially vulnerable to the medical consequences of HPV;not only cervical cancer and its precursor lesions but also unnecessary and potentially harmful interventions for false positive screening tests and diagnostic findings. The overall objective of our proposed program project is to provide scientific knowledge on HPV infections that will lead to evidence-based strategies for age-appropriate prevention of HPV-related cancers in women. We plan to accomplish this goal by undertaking three interdisciplinary research projects that will synergistically build on each other, and on our team's experience with molecular epidemiology studies of HPV infection and related precancerous lesions and cancers. Each project will be co-directed by one senior and one junior investigator, with one investigator having clinical expertise and the other having laboratory or epidemiological expertise. This oversight structure ensures high standards in the conduct of the clinical research while encouraging discovery through cross-fertilization of ideas. The projects will be supported by three cores: laboratory, biostatistics/epidemiology, and administration. Our aims focus on important unresolved scientific and clinical issues including the risk of reactivating versus new high-risk (HR) HPV infection in women 30 to 50 years of age (project 1), the natural history and potential consequences of CIN2 lesions caused by different HR-HPV genotypes (project 2), and the role of epigenetic changes in the persistence, progression, and regression of CIN2 (project 3). Finding from these studies will contribute to improved management strategies for women with HR-HPV-related precancerous and benign lesions, appropriate use of prophylactic HPV vaccines and HR-HPV diagnostic tests, and to the development of novel demethylating treatments. PROJECT 1: Title: Natural History of HPV Infections in Mid-Adult Women Project Leader: Winer, R PROJECT 1 DESCRIPTION (provided by applicant): While much is now known about the acquisition and early natural history of HPV infections in sexually active young women, little is known about HPV infections in mid-adult women. In particular, the risk of acquiring new high-risk (HR) HPV infections from new sex partners is undefined and the frequency of reactivating HR HPV infections that were acquired in adolescence or young adulthood is unknown. Furthermore, the risk of abnormal cytology associated with new versus reactivated infections is undefined. We will enroll 1,000 women between the ages of 30 to 50 who are faculty, staff, or students at the University of Washington and follow them with bi-annual clinical visits for two years. At each visit, a nurse practitioner will conduct a face-to-face medical and sexual behavior interview (supplemented with bi-weekly online sexual behavior diaries) and collect cervical specimens for Pap testing and for HPV genotyping and viral load testing. Serum for HPV antibody testing will be collected at the enrollment and exit visits. Women will also self-collect vaginal samples for HPV DNA testing at each visit, and a subset of 200 women will be selected to do monthly self collections between the month 6 and month 12 visits. The specific aims of this longitudinal study are to 1) define rates and determinants of newly acquired and reactivated type-specific HR HPV infections in mid-adult women;2) define the probability and determinants of reactivation in a subset of 200 women (with serologic evidence of prior infection and no recent new sex partners) followed with monthly vaginal self-collections for HPV testing for 6 months;and 3) compare the probability of abnormal cytology (atypical squamous cells of undetermined significance or greater [ASC-US+]) associated with newly acquired versus re-activated type-specific HR HPV infections. Findings from this project will inform clinician/patient interactions and development of prophylactic vaccine implementation and cervical cancer screening guidelines in populations of mid-adult women.